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Classification of anticancer drugs - A new system based on therapeutic targets

Article  in  Cancer Treatment Reviews · January 2004

DOI: 10.1016/S0305-7372(03)00116-6 · Source: PubMed

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CANCER TREATMENT REVIEWS 2003; 29: 515–523
doi:10.1016/S0305-7372(03)00116-6

ANTI-TUMOUR TREATMENT

Classification of anticancer drugs—a new

system based on therapeutic targets
Enrique Espinosa, Pilar Zamora, Jaime Feliu and
Manuel González Barón

Servicio de Oncologı´a Médica, Hospital La Paz, Madrid, Spain

The arrival of a great number of new antineoplastic agents has made it necessary to reclassify all of them. Anticancer drugs
may act at different levels: cancer cells, endothelium, extracellular matrix, the immune system or host cells. The tumour cell
can be targeted at the DNA, RNA or protein level. Most classical chemotherapeutic agents interact with tumour DNA,
whereas monoclonal antibodies and small molecules are directed against proteins. The endothelium and extracellular matrix
may be affected also by specific antibodies and small molecules.
C 2003 Elsevier Ltd. All rights reserved.

Key words: Antineoplastic drugs; chemotherapy; classification; monoclonal antibodies; new drugs; small molecules.

therapy. A global view is important to remember the

INTRODUCTION drugs and their mechanism of action and also for
teaching purposes. On the other hand, multidrug
Most patients with advanced solid tumours still die regimens usually include drugs belonging to differ-
of their disease. For this reason, new effective drugs ent groups to increase efficacy and decrease toxicity,
are needed and, in fact, new agents appear every at least whenever classical chemotherapy is con-
few months. The last years have witnessed the ap- cerned.
pearance of a great number of anticancer drugs, We hereby propose a new drug classification
many of which cannot be included in a simple based on the kind of target. Drugs may be directed at
classification. Classically, anticancer drugs were tumour cells or other elements involved in carcino-
grouped as chemotherapy, hormonal therapy and genesis, i.e., the endothelium and extracellular ma-
immunotherapy. Chemotherapy included a number trix, and the immune system. Potential host cells
a families defined by both their chemical structure such as the bone may also be targeted. Table 2 shows
and mechanism of action: alkylating agents, antibi- all these groups. The target may be located at the
otics, antimetabolites, topoisomerase I and II inhib- DNA, RNA or protein level. In general, chemother-
itors, mitosis inhibitors, platinum compounds and apy acts at the DNA level in tumour cells, whereas
others (Table 1). However, the group ‘‘others’’ has monoclonal antibodies and small molecules interact
expanded so much that this classification is no with proteins, either in the tumour cells or in other
longer useful. elements. Antisense oligonucleotides are the main
A drug classification serves two main objectives: drugs directed against mRNA.
the achievement of a comprehensive view of the It is beyond our scope to describe the mechanism
available drugs and the design of combination of action of every drug in detail. In some cases, the
precise mechanism is still uncertain. Besides, some
Correspondence to: Enrique Espinosa, Servicio de Oncolog
ıa
of the compounds we shall mention may not go
M
edica, Hospital La Paz, Po de la Castellana, 261-28046 Madrid, beyond phase III trials. We would like to offer a
Spain. Fax: +34-917-277-118; E-mail: eespinosa00@terra.es useful tool to classify both available and forthcoming

0305-7372/$ - see front matter C 2003 ELSEVIER LTD. ALL RIGHTS RESERVED.
516 E. ESPINOSA ET AL.

TA B L E 1 Classical classification of anticancer drugs DRUGS DIRECTED AGAINST TUMOUR DNA

Chemotherapy Alkylators
Antibiotics The drugs may act on DNA either by breaking the
Antimetabolites helix itself, interfering with DNA-related proteins, or
Topoisomerases inhibitors modifying the expression of specific genes. Most
Mitosis inhibitors
classical anticancer agents have one of these mech-
Other
anism of action, and new drugs are being incorpo-
Hormonal therapy Steroids rated every year (Tables 3a and 3b).
Anti-estrogens
Anti-androgens
LH–RH analogs
Anti-aromatase agents DNA helix
Immunotherapy Interferon
Interleukin 2 Alkylating agents were the first compounds identi-
Vaccines fied to be useful in cancer. They form a variety of
interstrand cross-links called adducts, that alter
DNA structure or function. The most common site of
alkylation is the N-7 position of guanine, but it
anticancer drugs, even when a global classification varies depending on the family of drugs. Alkylators
might have some exceptions or could be very sche- belong to one of several families: nitrogen mustards,
matic in some instances. We have restricted the in- nitrosoureas, triazenes, platinum compounds and
clusion of new compounds to those under clinical antibiotics (Table 3a) (1).
development.

TA B L E 2 Proposed new classification

Target
Tumour DNA Non-specific
DNA break: chemotherapy
DNA-related proteins: chemotherapy
Specific
Hormonal therapy, retinoids
Interferon a
Gene therapy
RNA Antisense oligonucleotides
Proteins Membrane receptors
Extracellular domain: MoAb
Intracellular domain: small molecules
Cytoplasm
Intracellular pathways: small molecules
Tubulin: chemotherapy

Endothelium (*) DNA Combretastatin

Proteins Monoclonal antibodies
Small molecules

Extracellular matrix MMPs MMPs inhibitors

Other elements Monoclonal antibodies and small
molecules

Immune system Lymphocytes and Interferons

macrophages Interleukin2
Vaccines

Host cells Bone cells Bisphosphonates, osteoprotogerin

* In this group, antisense therapy might also be developed in the future.

MoAb, monoclonal antibodies and MMPs, metalloproteinases.
CLASSIFICATION OF ANTICANCER DRUGS 517

TA B L E 3a Drugs directed against tumour DNA: chemotherapy

DNA break
Nitrogen mustards Cyclophosphamide, ifosfamide, melphalan, chlorambucil, bendamustine Cross links
Nitrosoureas BCNU Cross links
Triazenes Dacarbazine, temozolomide Cross links
Antibiotics Bleomycin, mitomycin Cross links
Platinum compounds Cisplatin, carboplatin, oxaliplatin Cross links

DNA-related proteins
Antibiotics Anthracyclines: doxorubicin, epirubicin, idarubicin, mitoxantrone Free radicals & £ Topo II
Podophillotoxins Etoposide £ Topo II
Topo I inhibitors Topotecan, irinotecan, rubitecan £ Topo I
Antimetabolites Antifolates: methotrexate, trimetrexate £ DHFR & other enzymes
Fluoropyrimidines (5FU, ftorafur, capecitabine) and raltitrexed £ TS
Pemetrexed £ DHFR, TS, FTRG
Cytarabine, fludarabine £ DNA polymerase & RR
Gemcitabine £ RR
Adenosine analogs: deoxycoformycin, cladribine £ Adenosine-deaminase
Other Ecteinascidin £ Transcription factors

Topo, topoisomerase; DHFR, dihydrofolic reductase; TS, thymidilate synthase; FTRG, formyltransferase ribonucleotide glycinamide;
RR, ribonucleotide reductase; £, inhibition.

TA B L E 3b Drugs directed against tumour DNA: modifiers of specific genes

Steroids Prednisolone, dexamethasone Union to specific receptors, transcriptional
interaction with specific genes
Antihormones Antiestrogens: tamoxifen, fulvestrant
Antiandrogens: flutamide,
bicalutamide
Antiaromatase: anastrozole, letrozole,
exemestane
LH-RH agonists: goserelin,
tryptorelin, buserelin
Retinoids ATRA, fenretidine, bexarotene
Interferon a
Gene therapy

There are some new experimental agents among

the alkylators, such as bendamustine or tira- DNA-related proteins
pazamine. Bendamustine, a nitrogen mustard
compound, has activity in lymphomas (2–4). Tira- Topoisomerase I and II inhibitors, antimetabolites
pazamine is activated in hypoxic cells and en- and ecteinascidin could be grouped together as
hances the cytotoxicity of radiation, cisplatin and drugs directed at protein–DNA complexes, because
the taxanes (5,6). It has been used for the treatment they do not bind directly to DNA (1).
of non-small cell lung cancer and head and neck The anthracyclines (doxorubicin and their analogs
tumours. epirubicin and idarubicin) inhibit topoisomerase II
Some antibiotics also belong to the group of al- and form free radicals. Mitoxantrone, although
kylators: bleomycin and mitomycin C. The anthra- synthetic, can be regarded as an anthracycline. The
cyclines have a different mechanism of action and main epipodophillotoxin, etoposide, also inhibits
are included in the next group. topoisomerase II.
518 E. ESPINOSA ET AL.

Topoisomerase I transiently breaks a single strand specific genes does not mean that this activity is re-
of DNA during DNA replication, thereby reducing stricted to tumour cells.
torsional strain. Inhibitors of this enzyme derive Gene therapy also targets specific genes, but in
from camptothecin. This family has grown rapidly this case the mechanism of action differs substan-
in recent years. In addition to topotecan and irino- tially from that of the hormones. Genes are intro-
tecan, new experimental agents could join the family duced in vectors to either repair or block specific
in the near future, for instance rubitecan (7,8), lur- DNA sequences.
totecan (9,10) or exatecan (11,12).
On the other hand, antimetabolites interfere with
enzymes that contribute to DNA synthesis. In this
group we have antifolates, fluoropyrimidines, ral-
DRUGS DIRECTED AGAINST TUMOUR RNA
titrexed, cytarabine, gemcitabine, and adenosine
analogs (fludarabine, pentostatin, cladribine). A number of anticancer drugs such as the fluoro-
Pemetrexed has recently been incorporated to the pyrimidines and platinum compounds interfere
clinic. This drug shows activity in non-small cell with RNA synthesis. However, they mainly act by
lung cancer, breast cancer, mesothelioma and head binding to DNA. The major representatives in this
and neck tumours (13–15). Table 3a indicates the group are antisense oligonucleotides. These mole-
target enzyme for each antimetabolite. cules are directed against specific mRNAs. The
A marine derivative, ecteinascidin or ET-743, has mRNAs of bcl-2, myb, p53, mdm2, Her-2 and
a unique mechanism of action. Formerly thought to methyltransferase-1 have been targeted with these
be an alkylator, recent investigations have shown oligonucleotides (19–25). The synthesis of antisense
that it blocks transcriptional factors—such as TC- oligonucleotides is complex and improved methods
NER or Sp1—and seems to affect RNA polymerase to deliver the compound in the target are needed
II-mediated gene transcription (16). Ecteinascidin (25–27). These problems are delaying the develop-
has been used in patients with refractory sarcomas ment of antisense therapy. Another drug in this
(17). group is angiozyme, which blocks the mRNA of the
vascular endothelial growth factor (28,29).

Specific genes
DRUGS DIRECTED AGAINST PROTEINS IN
The classical representatives in this group are hor- THE TUMOUR CELL
monal agents. Steroids, antihormones and retinoids
share a common mechanism of action because they In the last decade, a great number of compounds
modify the expression of specific genes (Table 3b). have joined this group, mainly monoclonal anti-
Steroid hormones, such as glucocorticoids, bind to bodies and small molecules. They are all very spe-
receptor proteins in the cytoplasm or nucleus to cific and their effect is cytostatic rather than
form a hormone–receptor complex. This complex cytotoxic. They can bind to membrane receptors or
has the capacity to activate regulatory sequences in cytoplasmic proteins.
DNA. Antioestrogens and antiandrogens block re-
ceptors of oestrogens and androgens, respectively.
These receptors are ligand-regulated transcription
factors located in the nucleus. The antiaromatase Receptors in the tumour membrane
agents anastrozole, letrozole and exemestane act in
the cytoplasm, mainly in tumour cells but also in Two groups may be distinguished: monoclonal an-
peripheral tissues. tibodies and small molecules. The former block the
LH–RH analogs bind to a specific membrane re- extracellular domain of the receptor, whereas the
ceptor linked to a G protein in the hypothalamus. latter cross the membrane and inhibit the intracel-
However, the ultimate effect takes place in the tu- lular domain, usually a tyrosin-kinase (Table 4). The
mour cell, and for this reason the analogs should be term ‘‘small molecule’’ may be misleading, because
grouped together with the other hormones (Table 2). classical chemotherapy compounds are also small in
The antitumour activity of interferon a appears to size, but it allows the distinction with monoclonal
be due to a combination of direct antiproliferative as antibodies.
well as indirect immune-mediated effects. It has also The first antitumour antibodies were directed
antiangiogenic effects mediated through interferon against lymphoid antigens, such as CD20 and CD52.
gamma (18). Thus, this drug may appear in several Some of them combine the antibody with an isotope
groups in our classification. Activity over some to increase efficacy (30–34). These highly active
CLASSIFICATION OF ANTICANCER DRUGS 519

TA B L E 4 Drugs directed against the membrane receptors of

the tumour cell
Extracellular domain
Monoclonal antibodies
Rituximab Anti CD20
Ibritumomab-I*, Anti CD20
tositumomab-I*
Alemtuzumab Anti CD52
Trastuzumab Anti Her-2
Cetuximab Anti EGFR (Her-1)
Intracelular domain
Small molecules
ZD-1839 (gefitinib) £ Tyrosin-kinase EGFR
OSI-774 (erlotinib) £ Tyrosin-kinase EGFR Figure 1 Metabolic pathways currently used by small
PKI-166 £ Tyrosin-kinase EGFR and molecules inside the cancer cell.
Her-2
CI-1033 £ Tyrosin-kinase of all Her
one of the most active drugs in chronic myeloid
leukaemia and in gastrointestinal stromal tumours.
Other drugs are aimed at the ras or the phosphati-
compounds have expanded the possibilities of dyl-inositol pathways, as well as the proteasome and
treatment in patients with refractory lymphomas the cyclin-dependent kinases. With few exceptions,
and are now being evaluated in first- line therapy. these agents are now in the first steps of clinical
New antibodies are under investigation at this mo- development. Table 5A includes some of them.
ment: the anti-CD33 gemtuzumab and the anti-CD22 Ras is activated by farnesyl transferase. Once ac-
epratuzumab, for instance (35,36). tivated, the ras protein activates raf and MEK.
The main antibodies for carcinomas are trast- Farnesyl-transferase inhibitors act as false metabo-
uzumab (37,38) and cetuximab (39,40). Trastuzumab lites of this enzyme, for instance, lonafarnib and
is available for the treatment of Her-2 positive breast
tumours, either alone or in combination with che-
motherapy, and new possible indications are being TA B L E 5 Drugs acting in the cytoplasm of the tumour cell
studied. On the other hand, an anti-MUC antibody
(A) Inhibitors of intracellular pathways in tumour cells
could be used in the future as a vaccine in patients Imatinib £ Tyrosin-kinase of
with carcinomas (41). bcr/abl and c-kit
Small molecules bind to receptors of the epider-
mal growth factor family. Some of them are specific Ras
SCH-6636 (lonafarnib), R115,777 Ras mimetic
for EGFR (Her-1), such as gefitinib (ZD-1839) (42–43)
BMS-214662 £ Farnesyl transferase
or OSI- 774 (44). Gefitinib is the only member of the
CI-1040 £ MEK
group that has been tested in phase III trials so far. It
obtains responses as single agent in non-small cell Phosphatidyl-inositol and PKC
lung cancer and head and neck tumours. PKI-166 CI-779 £ mTOR
inhibits both Her-1 and Her-2 (45). CI-1033 is an ir- Bryostatin, PKC-412 £ Protein-kinase C
reversible inhibitor of all the epidermal growth fac- Proteasome/chaperones
tor receptors (46). PS-341 £ Proteasome
17-AAG (ansamycin) Increases degradation of
HSP90

Intracellular pathways in tumour cells Cyclin-dependent kinases

Flavopiridol, CYC-202 £ CDKs
UCN-01 £ CDK-2
A number of metabolic pathways carry proliferation
signals to the nucleus. Although we shall comment (B) Inhibitors of tubulin
on them separately, all of them are interrelated. Vinca alkaloids: vincristine, £ Microtubule
These pathways are activated by growth factors and vinblastine, vindesine, vinorelbine polymerization
a few of them have been targeted with specific Taxanes: paclitaxel, docetaxel, Microtubule stabilization
drugs. Figure 1 shows a scheme of the pathways that BMS-275183
are being used in cancer therapeutics. The better Epothilones: BMS-257000,
known drug in this group is imatinib, which inhibits BMS-310705, EPO-906
the tyrosine kinase of bcr/abl and c-kit (47,48). It is
520 E. ESPINOSA ET AL.

R115,777 (49,50). There are also inhibitors of raf TA B L E 6 Drugs directed against the endothelium and the
(BAY 43-9006) and MEK (CI-1040) (51,52). extracellular matrix
The phosphatidyl-inositol pathway starts with the Endothelial growth factors
serin threonine PI-3K, which is connected with Thalidomide £ VEGF, bFGF, TGF-a
mTOR through PKB/Akt. MTOR controls apoptosis Carboxiamide-triazol (CAI) £ Synthesis of VEGF
and is related to the balance between cellular ca-
Receptors of endothelial cells
tabolism and anabolism. Specific drugs in this Bevacizumab Anti VEGFR
pathway are rapamycin derivatives such as CCI-779, SU-5416, SU-6668, endostatin £ Tyrosin-kinase of VEGFR
which inhibits mTOR (53). PI-3K is also connected
with protein-kinase C, a family of enzymes that ac- Extracellular matrix
Marimastat, AG-3340 £ Metalloproteinases
tivate the transcription factor NF-jB. Protein-kinase
(prinomastat), AE-941
C is inhibited by bryostatin (54,55) and PKC-412 (56).
(Neovastat)
The proteasome—a group of enzymes that de- Vitaxin Anti integrin
grade proteins—is inhibited by PS-341 (57,58). On ABT-510 Mimetic of thrombospondin
the other hand, the chaperones exert the opposite
function, i.e., they protect proteins from degrada-
tion. Geldanamycin derivatives such as 17-AAG in-
crease the degradation of one of the main Endothelium
chaperones, heat shock protein 90 (59,60).
Finally, flavopiridol and CYC-202 (a roscovitine The main endothelial growth factors—vascular en-
derivative) inhibit cyclin-dependent kinases (61,62). dothelial growth factor (VEGF)and basic fibroblast
The staurosporin compound UCN-01 inhibits CDK-2 growth factor (bFGF)—are inhibited by thalido-
selectively (63,64). mide (68,69). Another inhibitor specific for VEGF is
carboxyamido-triazole (70,71). Interferon a also re-
duces VEGF synthesis in tumour cells, but this effect
seems to be mediated through interferon gamma
Tubulin
(18,72,73). Cyclo-oxygenase 2 may stimulate endo-
thelial growth, hence one of the possible mecha-
Tubulin contributes to the maintenance of cell shape, nisms of action of COX-2 inhibitors (74,75).
intracellular transport and mitosis, so drugs inter- With regard to VEGF receptors, the monoclonal
fering with tubulin are grouped here in the present antibody bevacizumab binds to all of these receptors
classification. The vinca alkaloids bind to specific (70,76,77). SU-5416 is a small molecule binding to the
sites on tubulin and prevent polymerization of tu- tyrosine kinase of VEGFR-1 and VEGFR-2 (70,78). It
bulin dimers, thereby disrupting the formation of also binds to platelet derived growth factor receptor
microtubules. The taxanes have a different binding and c-kit. Clinical trials with SU-5416 in haemato-
site and stabilize microtubules: this unusual stability logical malignancies and colorectal cancer have been
inhibits the normal reorganization of the microtu- initiated. Another small molecule, SU-6668, binds to
bule network. Oral formulations of taxanes will VEGFR, bFGFR and platelet derived growth factor
improve convenience if they prove to be as active as receptor (PDGFR) (79,80).
the parent drugs (65). The epothilones are a new Finally, combretastatin inhibits the mitotic spin-
group of tubulin-stabilizing agents. Preclinical dle in the endothelium and induces apoptosis
studies have shown promising activity of these (81,82).
compounds, but the results of phase II and III clin-
ical trials are not still available (66,67). Table 5B
shows all these drugs. Extracellular matrix

Activation of MMPs in tumours facilitates invasion

and is an essential step in angiogenesis. MMPs may
DRUGS ACTING ON THE ENDOTHELIUM also stimulate the release of VEGF, bFGF and insulin
AND EXTRACELLULAR MATRIX growth factor. A number of MMP inhibitors are
currently under clinical investigation (83). Most of
Compounds directed against the endothelium in- them are synthetic inhibitors of the enzyme activity,
hibit either endothelial growth factors or the recep- such as marimastat (84–86), prinomastat or BAY 12-
tors of such factors. On the other hand, most drugs 9566 (83). Tetracycline derivatives such as neovastat
acting in the extracellular matrix inhibit metallo- also down regulate the production, inhibit the acti-
proteinases (MMPs). They all have antiangiogenic vation and increase the degradation of MMPs
effects (Table 6). (87,88).
CLASSIFICATION OF ANTICANCER DRUGS 521

Apart from MMPs, other elements of the extra- 7. Giovanella BC, Stehlin JS, Hinz HR, Kozielski AJ, Harris NJ,
cellular matrix could be targeted as a form of anti- Vardeman DM. Preclinical evaluation of the anticancer
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Some drugs are directed to organs that may harbour
Dihel LC, et al. Antitumor efficacy, pharmacokinetics, and
tumour cells. At present, these only relate to agents biodistribution of NX 211: a low-clearance liposomal
that inhibit bone cell function and the bone micro- formulation of lurtotecan. Clin Cancer Res 2000; 6(7):
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